Anti-tumor immune responses are a facet of the tissue-specific autoimmune phenomenon. The generation of immune responses to tissue rejection antigens, therefore, represents an important conceptual approach in cancer immunotherapy. Tumor-associated carbohydrate antigens (TACAs) are potential tissue rejection antigen targets that display tissue-specific variation, with both T cells and antibodies recognizing mono- and disaccharide constituents of TACA.
Glycosylation regulates NK cell-mediated effector function through the PI3K pathway. Interference with N-glycosylation has been shown both to reduce the membrane expression of MHC class I and to increase the in vitro sensitivity of tumor cells to NK cell killing. Early on it was recognized that compounds that inhibit glycosylation pathways could affect the growth of tumor cells in tumor bearing animals. Castanospermine, swainsonine and tunicamycin block different steps in the pathway of glycoprotein processing yet each are potent inhibitors of tumor cell dissemination and tumor colonization. This suggested blocking at one of at least two steps could have beneficial effects on tumor cell growth. The antimetastatic effect of tunicamycin may be related to interference in tumor cell-extracellular matrix interactions, whereas treatment with castanospermine or swainsonine appears to block at a stage distal to initial tumor cell arrest. Swainsonine in particular is interesting as it inhibits the formation of N-linked complex oligosaccharides with this inhibition correlative with enhancement with NK cell function. Consequently inhibitors of N- as well as O-linked glycosylation should be useful for the treatment of cancer by affectively resetting NK functional activity by disruption of negative signals; given that inhibitors can be specifically targeted to tumor tissue. More recently Bortezomib (Velcade) as a proteasome inhibitor is purported to increase the sensitivity of tumor cells to NK activity by down modulating MHC Class I expression. N-linked glycosylation does not impair proteasomal degradation but affects Class I MHC presentation. Conversion of the glycosylated Asn (N) into Asp (D) in proteasomal breakdown products is mediated by PNGase. PNGase can act following proteasomal degradation. As a result, class I MHC antigen presentation is markedly reduced.
The orchestration of glycan remodeling and galectin-1 up-regulation by the tumor suppressor p16INK4a pancreatic carcinoma cells to reconstitute susceptibility to anoikis underscores the potential and tight control of this lectin. Anti-glycan antibodies can function like lectins, mediating cell death signals and cell growth signals. Other Galectins can promote NK cell-mediated anti-tumor activity by expanding unique phenotypes. Co-culture of naïve NK cells with macrophages from Gal-9-treated mice resulted in enhanced NK activity, although Gal-9 itself did not enhance the NK activity. Antibodies can do the same. Expansion of natural killer cells in mice transgenic for IgM antibody to ganglioside GD2 was demonstrated to prolong survival after challenge with syngeneic tumor cells. Depletion of NK cells with anti-asialo GM1 rabbit serum reduced or abrogated the observed anti-tumor effects, suggesting that NK cells play a major role in tumor eradication or suppression. These results suggest that NK cell responses may be specifically enhanced, after vaccination, from CMP-specific B cells in a manner that confers a NK phenotype for local expansion of NK activity for the tumor.
United States Patent Publication Nos. 20030017497 and 20050181987 each disclose peptide mimotopes of carbohydrate antigens and methods of using such peptides in the treatment of cancer. Carbohydrate mimetic peptides (CMPs) stimulate immune responses targeting TACAs that effectively promote tumor growth inhibition in mouse models of cancer. CMPs are broad-spectrum immunogens, inducing responses to multiple TACAs and therefore obviating the need for multivalent carbohydrate-based vaccines. Among CMPs are those that use aromatic-aromatic and hydrophobic interactions as critical chemical forces that modulate binding of the CMPs to anti-carbohydrate antibodies. The tumor growth inhibition upon immunization with CMPs having a central motif of Tyr-Arg-Tyr or Trp-Arg-Tyr has been observed.
Preclinical studies of carbohydrate mimetic peptide vaccines for breast cancer and melanoma are disclosed in Monzavi-Karbassi, B. et al. (2007) Vaccine 27:3022-3031. The immunogen is includes a P10s multiple antigen peptide (MAP) form as well as three other peptides P10, CMP 106 and CMP 107, each also provided as a MAP form. A MAP form of a peptide is a polypeptide having multiple repeating sequences of the peptide. MAP forms of a peptide typically have 2-10 copies of the peptide.
Hennings, L. et al. (2011) Cancers 3:4151-4169 disclose that carbohydrate mimetic peptides augment carbohydrate-reactive immune responses in the absence of immune pathology. Peptides P10, CMP 106 and CMP 107 are referred to and data show immune responses against CMPs do not have harmful effects on normal cells that contain carbohydrates.